Considerable interest has been shown in recent years in the use of prostaglandin (PG) precursors in medicine.
For various reasons it is not practical to administer naturally-occurring prostaglandins such as PGE 1 and PGE 2 to patients. Consequently, considerable attention has focussed on the use of prostaglandin precursors including linoleic acid (9,12-octadecadienoic acid), .gamma.-linolenic acid (6,9,12-octadecatrienoic acid) and dihomo-.gamma.-linolenic acid (5,8,11-eicosatrienoic acid), conversion in the body being believed to be as follows: ##STR1##
Ageing is characterised by a number of changes in body structure, physiology and biochemistry. There are for example increased susceptibilities to cardiovascular diseases and cancer. One of the key features of ageing is loss of the normal behaviour of the immune system. The body's immune system, usually directed outwards to invading organisms, becomes increasingly directed inwards, attacking the body's own substance. This immune failure appears to be due to progressive malfunction of cells known as T-lymphocytes and especially of a subset of these cells known as T suppressor lymphocytes (R. L. Walford, Amer. J. Clin. Pathol. 74: 247, 1980).
Many attempts have been made to prolong life in both human and animal experiments but only one technique has proved consistently if modestly successful. In several different studies, a reduced total food intake has been found to prolong animal life and to slow down the development of the abnormalities of the immune system (R. L. Walford, Amer. J. Clin. Pathol. 74: 247, 1980). The way in which food restriction works is unknown.
It is suggested by the present inventor that a key factor in the development of ageing is loss of the ability of the body to make .gamma.-linolenic acid (GLA) from dietary cis-linoleic acid. Thus, by-passing this block by providing GLA directly, for example by mouth, by inunction through the skin, or by injection will slow down or prevent some of the processes of ageing and even reverse to some extent changes which have already occurred. Similar effects will be achieved by providing DGLA, to which GLA is rapidly converted in the body.
The evidence is as follows:
1. The ability of animals' tissues to convert linoleic acid to GLA falls with age. The rates at which this happens differ from organ to organ. In the rat testis the ability to make GLA is sharply reduced within a few months whereas in the rat liver it falls only after about one year. (S. Ayala et al, J. Lipid Res. 14: 296, 1973: R. O. Peluffo et al, Am. J. Physiol. 218: 669, 1970).
2. A loss of the ability to make GLA of course leads to loss of the ability to make further metabolites of GLA, notably PGE 1. PGE 1 is necessary for T-lymphocyte function and a lack of it is an explanation for the T-lymphocyte failure seen in ageing. PGE 1 also lowers cholesterol levels, lowers blood pressure and reduces the risk of thrombosis (D. F. Horrobin, Med. Hypotheses 6: 785-800, 1980): a lack of it is an explanation for the increased risk of diseases of the heart and circulation with ageing. PGE 1 in laboratory animals can normalise cancer cells (D. F. Horrobin, Med. Hypotheses 6: 469, 1980) and a lack of PGE 1 is an explanation for the increased risk of cancer with ageing.
3. In experiments designed to look at the effects of calorie restriction on essential fatty acid metabolism, moderate calorie restriction in rats increased by over 300% the ability of the animals to convert linoleic acid to GLA (Faas et al, Lipids 15: 953-61, 1980).
4. High alcohol intake (D. F. Horrobin, Med. Hypotheses 6: 929, 1980) and diabetes (R. R. Brenner, Molecular Cellular Biochem 3: 41, 1974) both lead to loss of the ability to convert linoleic acid to GLA. Both are also associated with a risk of accelerated ageing.
5. GLA in the form of Evening Primrose oil has been found to correct defects which can be associated with ageing:
(a) GLA in the form of Evening Primrose oil has improved the clinical status of humans with eczema and with Sjogren's syndrome and of animals with adjuvant arthritis. All these conditions are associated with defective T-lymphocyte function.
(b) GLA in the form of Evening Primrose oil can lower blood pressure and blood cholesterol. Elevated blood pressure and cholesterol are commonly associated with ageing.
Thus a number of factors have led the present inventor to propose that development of the above and other physical manifestations of ageing may be slowed down or stopped, and some even reversed, by the provision of adequate amounts of either GLA or DGLA. However such a proposal, while new in the sense of giving the GLA or DGLA for a new purpose, is something that has been done before for other reasons. Everyone is ageing, and, among at least the older people given the acids, there will have been some showing the physical manifestations of ageing discussed.
The inventor however specifically believes that among the numerous recognised essential nutrients rutin, troxerutin and other bioflavonoids have a particularly significant effect in the ageing content. Rutin has the specific action in both the 1-series and 2-series of blocking the conversion of PGE to PGF. There is substantial evidence that PGE's (especially PGE 1) are the most desirable PG's in the body, compared for example to the related thromboxanes which tend to be toxic and the other PG's which have mixed good and bad effects, and this is especially so in the ageing context. The specific effect of rutin in blocking a route by which PGE's are lost is thus highly significant.
Thus the present invention lies in compositions and use of essential fatty acids, and most particularly .gamma.-linolenic acid and dihomo-.gamma.-linolenic acid and physiologically functional derivatives thereof, with materials blocking PGE to PGF conversion, particularly rutin, troxerutin and other bioflavonoids, either as such or (as is discussed further herein) in conjunction with zinc, .beta.-lactam antiobiotics or other materials influencing the 1-series/2-series PG balance in the body in favour of 1-series PG's, herein referred to as 1-series PG enhancers.
The 1-series PG enhancers are discussed at length in the present inventor's published European Patent Specifications Nos. 0 003 407 (zinc and .beta.-lactam antibiotics), 0 004 770 (penicillamine, phenformin or levamisole and a group of other materials including colchicine and vinca alkaloids); and 0 019 423 (Vitamin C, ethyl alcohol, and opiate antagonists). The disclosure of these specifications, both as to materials proposed and as to amounts suitable for administration, for use in conjunction with .gamma.-linolenic acid or dihomo-.gamma.-linolenic acid, is incorporated herein by reference. Not all of the materials, of course, would be materials of choice in view of their other effects, but they are nevertheless effective in the present context.
Amounts in which rutin, troxerutin and other bioflavonoids may suitably be administered are for example 10 mg-10 g daily preferably 50-250 mg. Amounts for other materials are discussed elsewhere herein. For the essential fatty acids, calculations as to what doses are likely to be adequate are based on what is known about linoleic acid requirements. In young animals and humans a minimum of 1% of total calorie intake is desirable in the form of linoleic acid. Many authorities have argued that this is too low, especially for normal brain and immune function and have suggested that 5% of total calorie intake of linoleic acid is required. The following calculations have assumed that most of this linoleic acid can be converted to GLA under normal conditions in young animals and that with ageing the body may totally lose its ability to make GLA. 2.2 grams of GLA would provide 20 calories or 1% of the calorie intake of an adult eating 2000 calories worth per day. 22 grams of GLA would provide 200 calories or 5% of the calorie intake of an adult eating 4000 calories per day. If the body is producing no GLA even a small amount may be helpful and the suggested minimum daily dose is therefore 20 to 50 mg. On the other hand there could be losses for one reason or another and the suggested maximum dose is 10 to 100 grams. The preferred dose range is 1 gram to 10 grams per day. DGLA or esters or other derivatives of GLA or DGLA can be used instead, when the above amounts shall be recalculated but on the GLA equivalent.